IgA nephropathy (IgAN) is characterized by IgA1-containing immune complexes (IC) in the glomerular mesangium. Proliferation of mesangial cells (MC) and extracellular matrix (ECM) expansion occur from early stages, progressing to glomerular and interstitial sclerosis and development of end-stage renal disease in 30-40% patients within 20 years. IgA1 containing deposits patients produce galactose-deficient O- linked glycans in the hinge region of IgA1. This aberrantly glycosylated IgA1 is bound to antibodies (IgG, IgA1) with anti-glycan specificity in CIC. We postulated that these CIC deposit in the mesangium. Highly undergalactosylated IgA1 was detected in IgAN mesangial deposits which support this hypothesis Our Preliminary Studies show that CIC with aberrantly glycosylated IgA1 from IgAN patients (IgAN-CIC) bound to MC in vitro and activated them. In four Specific Aims, we propose to test the hypothesis that CIC containing undergalactosylated IgA1 are involved in the pathogenesis of IgAN. In Specific Aim 1, we will examine presence and composition of these CIC in patients with familial and non-familial IgAN, and in non-IgAN glomerulonephritides controls and healthy individuals, and we will study binding as well as receptors involved in the binding of these IgAN-CIC (proliferation, apoptosis, cytokine synthesis, formation of reactive oxygen species). With selected samples of CIC (based on properties and activities of the CIC), we will identify MC genes induced or repressed by CIC. In Specific Aim 3, we will examine whether contemporaneously collected renal biopsies parallel the in vitro observed effects of CIC on MC and whether the same IgG and IgA receptors are expressed. Furthermore, results of Specific Aim 2 will identify other potential targets (IgAN- specific genes, ECM, up-regulated genes, etc.) In Specific Aim 4, we will study mechanisms of activation of MC by CIC and we will examine whether MC activation can be prevented by inhibition of CIC binding or by inhibition of signaling by the bound CIC. Understanding how the IgAN-specific IC are generated and how they bind to MC and discovering the key signals triggering the chain of events in MC that lead to IgAN may offer potential new therapeutic targets. Considering that current IgAN therapies are not especially effective, new pharmacological intervention would be beneficial.